SUMMARY Antibody-mediated therapies are an attractive alternative to current smoking cessation strategies because antibodies target the drug itself to prevent its crossing the blood brain barrier while exhibiting far fewer side effects. To date, nicotine vaccines have met with limited success in clinical trials due to their low immunogenicity. Like most subunit vaccines, they have historically suffered from poor efficacy due to their monomeric nature. Our approach overcomes this limitation by using Hafion?s polyvalent adjuvant fusion technology (Haf) wherein optimally sized hyaluronic acid (HA) is conjugated to a subunit vaccine to create a polyvalent HA-antigen nanoparticle designed for uptake by dendritic cells and subsequent trafficking to germinal centers in the lymph nodes to elicit maximum immunological memory. This proposal will bring together senior investigators from Hafion LLC, Design-Zyme LLC, and the University of Kansas. Together, we will combine the recent successes of a nicotine hapten, a self-adjuvating subunit antigen and the formation of nanoparticles to develop a nicotine vaccine that provides long-term immunological memory. Our approach improves upon the current design of nicotine vaccines by purposefully eliciting immunological memory to nicotine. To do this, Hafion is combining (1) a customized nicotine hapten that will be (2) linked to our proprietary adjuvant + HA complex known to elicit immunological memory (Design-Zyme LLC) by (3) the attachment of a carrier protein antigen that confers broad protection against multiple Salmonella serotypes. The S. enterica carrier protein antigen is a subunit vaccine developed by the Picking Laboratory. The goal of this SBIR is to create a safe, effective nicotine vaccine with additional bacterial pathogen protection suitable for animal testing and eventual use in FDA clinical trials. This project will demonstrate feasibility by assembling complete nicotine + Salmonella vaccine nanoparticles which will then be tested for efficacy, antibody affinity and long-term immunogenicity against nicotine and Salmonella in Phase I. Phase II of this proposal will involve studies to prepare the vaccine candidate for clinical trials as well as address larger scale production using GLP and GMP practices.